Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNJG99Z)

• DOT Name: Fanconi anemia group M protein (FANCM)
• Synonyms: Protein FACM; EC 3.6.4.13; ATP-dependent RNA helicase FANCM; Fanconi anemia-associated polypeptide of 250 kDa; FAAP250; Protein Hef ortholog
• Gene Name: FANCM
• Related Disease:
  Male breast carcinoma
  Advanced cancer
  Bloom syndrome
  Bone osteosarcoma
  Burkitt lymphoma
  Chronic fatigue syndrome
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Epithelial ovarian cancer
  Hereditary breast carcinoma
  Male infertility
  Neoplasm
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Spermatogenic failure 28
  Triple negative breast cancer
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Azoospermia
  Female hypogonadism
  Head and neck cancer
  Myelodysplastic syndrome
  Pancytopenia
  Fanconi's anemia
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
  Breast cancer
• UniProt ID: FANCM_HUMAN
• PDB ID: 4BXO; 4DAY; 4DRB; 4E45; 4M6W
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF02732 ; PF16783 ; PF00271
• Sequence:
  MSGRQRTLFQTWGSSISRSSGTPGCSSGTERPQSPGSSKAPLPAAAEAQLESDDDVLLVA
  AYEAERQLCLENGGFCTSAGALWIYPTNCPVRDYQLHISRAALFCNTLVCLPTGLGKTFI
  AAVVMYNFYRWFPSGKVVFMAPTKPLVTQQIEACYQVMGIPQSHMAEMTGSTQASTRKEI
  WCSKRVLFLTPQVMVNDLSRGACPAAEIKCLVIDEAHKALGNYAYCQVVRELVKYTNHFR
  ILALSATPGSDIKAVQQVITNLLIGQIELRSEDSPDILTYSHERKVEKLIVPLGEELAAI
  QKTYIQILESFARSLIQRNVLMRRDIPNLTKYQIILARDQFRKNPSPNIVGIQQGIIEGE
  FAICISLYHGYELLQQMGMRSLYFFLCGIMDGTKGMTRSKNELGRNEDFMKLYNHLECMF
  ARTRSTSANGISAIQQGDKNKKFVYSHPKLKKLEEVVIEHFKSWNAENTTEKKRDETRVM
  IFSSFRDSVQEIAEMLSQHQPIIRVMTFVGHASGKSTKGFTQKEQLEVVKQFRDGGYNTL
  VSTCVGEEGLDIGEVDLIICFDSQKSPIRLVQRMGRTGRKRQGRIVIILSEGREERIYNQ
  SQSNKRSIYKAISSNRQVLHFYQRSPRMVPDGINPKLHKMFITHGVYEPEKPSRNLQRKS
  SIFSYRDGMRQSSLKKDWFLSEEEFKLWNRLYRLRDSDEIKEITLPQVQFSSLQNEENKP
  AQESTTGIHQLSLSEWRLWQDHPLPTHQVDHSDRCRHFIGLMQMIEGMRHEEGECSYELE
  VESYLQMEDVTSTFIAPRNESNNLASDTFITHKKSSFIKNINQGSSSSVIESDEECAEIV
  KQTHIKPTKIVSLKKKVSKEIKKDQLKKENNHGIIDSVDNDRNSTVENIFQEDLPNDKRT
  SDTDEIAATCTINENVIKEPCVLLTECQFTNKSTSSLAGNVLDSGYNSFNDEKSVSSNLF
  LPFEEELYIVRTDDQFYNCHSLTKEVLANVERFLSYSPPPLSGLSDLEYEIAKGTALENL
  LFLPCAEHLRSDKCTCLLSHSAVNSQQNLELNSLKCINYPSEKSCLYDIPNDNISDEPSL
  CDCDVHKHNQNENLVPNNRVQIHRSPAQNLVGENNHDVDNSDLPVLSTDQDESLLLFEDV
  NTEFDDVSLSPLNSKSESLPVSDKTAISETPLVSQFLISDELLLDNNSELQDQITRDANS
  FKSRDQRGVQEEKVKNHEDIFDCSRDLFSVTFDLGFCSPDSDDEILEHTSDSNRPLDDLY
  GRYLEIKEISDANYVSNQALIPRDHSKNFTSGTVIIPSNEDMQNPNYVHLPLSAAKNEEL
  LSPGYSQFSLPVQKKVMSTPLSKSNTLNSFSKIRKEILKTPDSSKEKVNLQRFKEALNST
  FDYSEFSLEKSKSSGPMYLHKSCHSVEDGQLLTSNESEDDEIFRRKVKRAKGNVLNSPED
  QKNSEVDSPLHAVKKRRFPINRSELSSSDESENFPKPCSQLEDFKVCNGNARRGIKVPKR
  QSHLKHVARKFLDDEAELSEEDAEYVSSDENDESENEQDSSLLDFLNDETQLSQAINDSE
  MRAIYMKSLRSPMMNNKYKMIHKTHKNINIFSQIPEQDETYLEDSFCVDEEESCKGQSSE
  EEVCVDFNLITDDCFANSKKYKTRRAVMLKEMMEQNCAHSKKKLSRIILPDDSSEEENNV
  NDKRESNIAVNPSTVKKNKQQDHCLNSVPSGSSAQSKVRSTPRVNPLAKQSKQTSLNLKD
  TISEVSDFKPQNHNEVQSTTPPFTTVDSQKDCRKFPVPQKDGSALEDSSTSGASCSKSRP
  HLAGTHTSLRLPQEGKGTCILVGGHEITSGLEVISSLRAIHGLQVEVCPLNGCDYIVSNR
  MVVERRSQSEMLNSVNKNKFIEQIQHLQSMFERICVIVEKDREKTGDTSRMFRRTKSYDS
  LLTTLIGAGIRILFSSCQEETADLLKELSLVEQRKNVGIHVPTVVNSNKSEALQFYLSIP
  NISYITALNMCHQFSSVKRMANSSLQEISMYAQVTHQKAEEIYRYIHYVFDIQMLPNDLN
  QDRLKSDI
• Function: DNA-dependent ATPase component of the Fanconi anemia (FA) core complex. Required for the normal activation of the FA pathway, leading to monoubiquitination of the FANCI-FANCD2 complex in response to DNA damage, cellular resistance to DNA cross-linking drugs, and prevention of chromosomal breakage. In complex with CENPS and CENPX, binds double-stranded DNA (dsDNA), fork-structured DNA (fsDNA) and Holliday junction substrates. Its ATP-dependent DNA branch migration activity can process branched DNA structures such as a movable replication fork. This activity is strongly stimulated in the presence of CENPS and CENPX. In complex with FAAP24, efficiently binds to single-strand DNA (ssDNA), splayed-arm DNA, and 3'-flap substrates. In vitro, on its own, strongly binds ssDNA oligomers and weakly fsDNA, but does not bind to dsDNA.
• Tissue Specificity: Expressed in germ cells of fetal and adult ovaries. In fetal ovaries, it is present in oogonia but expression is stronger in pachytene stage oocytes. Expressed in oocytes arrested at the diplotene stage of prophase I during the last trimester of pregnancy and in adults . Expressed in the testis .
• KEGG Pathway: Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  PKR-mediated signaling (R-HSA-9833482)
  Fanconi Anemia Pathway (R-HSA-6783310)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Male breast carcinoma	DISUNQ2Q	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Bloom syndrome	DISKXQ7J	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Genetic Variation	[4]
Burkitt lymphoma	DIS9D5XU	Strong	Genetic Variation	[5]
Chronic fatigue syndrome	DIS34WJ5	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[9]
Hereditary breast carcinoma	DISAEZT5	Strong	Genetic Variation	[10]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Osteosarcoma	DISLQ7E2	Strong	Genetic Variation	[4]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[9]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[9]
Spermatogenic failure 28	DISHFI0N	Strong	Autosomal recessive	[13]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[14]
Acute monocytic leukemia	DIS28NEL	moderate	Biomarker	[15]
Acute myelogenous leukaemia	DISCSPTN	moderate	Biomarker	[15]
Azoospermia	DIS94181	moderate	Genetic Variation	[16]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[17]
Head and neck cancer	DISBPSQZ	moderate	Biomarker	[18]
Myelodysplastic syndrome	DISYHNUI	moderate	Biomarker	[15]
Pancytopenia	DISVKEHV	moderate	Biomarker	[15]
Fanconi's anemia	DISGW6Q8	Supportive	Autosomal recessive	[19]
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Supportive	Autosomal dominant	[16]
Breast cancer	DIS7DPX1	Disputed	Autosomal dominant	[13]

15 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Fanconi anemia group M protein (FANCM).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Fanconi anemia group M protein (FANCM).	[21]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Fanconi anemia group M protein (FANCM).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Fanconi anemia group M protein (FANCM).	[23]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Fanconi anemia group M protein (FANCM).	[24]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Fanconi anemia group M protein (FANCM).	[23]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Fanconi anemia group M protein (FANCM).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Fanconi anemia group M protein (FANCM).	[26]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Fanconi anemia group M protein (FANCM).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Fanconi anemia group M protein (FANCM).	[28]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Fanconi anemia group M protein (FANCM).	[30]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Fanconi anemia group M protein (FANCM).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Fanconi anemia group M protein (FANCM).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Fanconi anemia group M protein (FANCM).	[33]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Fanconi anemia group M protein (FANCM).	[34]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Fanconi anemia group M protein (FANCM).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Fanconi anemia group M protein (FANCM).	[29]

References

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• [2] Biallelic truncating FANCM mutations cause early-onset cancer but not Fanconi anemia.Genet Med. 2018 Apr;20(4):458-463. doi: 10.1038/gim.2017.124. Epub 2017 Aug 24.
• [3] Defining the molecular interface that connects the Fanconi anemia protein FANCM to the Bloom syndrome dissolvasome.Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4437-42. doi: 10.1073/pnas.1117279109. Epub 2012 Mar 5.
• [4] A comprehensive candidate gene approach identifies genetic variation associated with osteosarcoma.BMC Cancer. 2011 May 29;11:209. doi: 10.1186/1471-2407-11-209.
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• [7] Molecular Portrait of Metastasis-Competent Circulating Tumor Cells in Colon Cancer Reveals the Crucial Role of Genes Regulating Energy Metabolism and DNA Repair.Clin Chem. 2017 Mar;63(3):700-713. doi: 10.1373/clinchem.2016.263582. Epub 2016 Dec 22.
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• [9] FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine.BMC Med Genet. 2018 Jan 19;19(1):12. doi: 10.1186/s12881-018-0524-x.
• [10] The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants.Int J Cancer. 2019 Jun 1;144(11):2683-2694. doi: 10.1002/ijc.31992. Epub 2019 Jan 11.
• [11] Correction: A homozygous FANCM frameshift pathogenic variant causes male infertility.Genet Med. 2019 Jan;21(1):266. doi: 10.1038/s41436-018-0127-0.
• [12] A tumor suppressive DNA translocase named FANCM.Crit Rev Biochem Mol Biol. 2019 Feb;54(1):27-40. doi: 10.1080/10409238.2019.1568963. Epub 2019 Feb 4.
• [13] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [14] FANCM mutation c.5791C>T is a risk factor for triple-negative breast cancer in the Finnish population.Breast Cancer Res Treat. 2017 Nov;166(1):217-226. doi: 10.1007/s10549-017-4388-0. Epub 2017 Jul 12.
• [15] Germline Genetic Predisposition to Hematologic Malignancy.J Clin Oncol. 2017 Mar 20;35(9):1018-1028. doi: 10.1200/JCO.2016.70.8644. Epub 2017 Feb 13.
• [16] Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia. Am J Hum Genet. 2018 Aug 2;103(2):200-212. doi: 10.1016/j.ajhg.2018.07.005.
• [17] A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency.Elife. 2017 Dec 12;6:e30490. doi: 10.7554/eLife.30490.
• [18] The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies.BMC Cancer. 2017 Apr 4;17(1):239. doi: 10.1186/s12885-017-3211-y.
• [19] Fanconi Anemia. 2002 Feb 14 [updated 2021 Jun 3]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [20] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [21] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [22] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [23] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [24] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [25] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [26] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [29] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [30] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [31] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [32] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [33] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [34] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.